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CHAPTER 25
CARBOHYDRATES
T
he major classes of organic compounds common to living systems are lipids, proteins, nucleic acids, and carbohydrates. Carbohydrates are very familiar to us—
we call many of them “sugars.” They make up a substantial portion of the food
we eat and provide most of the energy that keeps the human engine running. Carbohydrates are structural components of the walls of plant cells and the wood of trees. Genetic
information is stored and transferred by way of nucleic acids, specialized derivatives of
carbohydrates, which we’ll examine in more detail in Chapter 27.
Historically, carbohydrates were once considered to be “hydrates of carbon”
because their molecular formulas in many (but not all) cases correspond to Cn(H2O)m. It
is more realistic to define a carbohydrate as a polyhydroxy aldehyde or polyhydroxy
ketone, a point of view closer to structural reality and more suggestive of chemical reactivity.
This chapter is divided into two parts. The first, and major, portion is devoted to
carbohydrate structure. You will see how the principles of stereochemistry and conformational analysis combine to aid our understanding of this complex subject. The remainder of the chapter describes chemical reactions of carbohydrates. Most of these reactions
are simply extensions of what you have already learned concerning alcohols, aldehydes,
ketones, and acetals.
25.1
CLASSIFICATION OF CARBOHYDRATES
The Latin word for “sugar”* is saccharum, and the derived term “saccharide” is the basis
of a system of carbohydrate classification. A monosaccharide is a simple carbohydrate,
one that on attempted hydrolysis is not cleaved to smaller carbohydrates. Glucose
972
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*“Sugar” is a combination of the Sanskrit words su (sweet) and gar (sand). Thus, its literal meaning is “sweet
sand.”
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25.2
Fischer Projections and D–L Notation
973
(C6H12O6), for example, is a monosaccharide. A disaccharide on hydrolysis is cleaved
to two monosaccharides, which may be the same or different. Sucrose—common table
sugar—is a disaccharide that yields one molecule of glucose and one of fructose on
hydrolysis.
Sucrose (C12H22O11) H2O
glucose (C6H12O6) fructose (C6H12O6)
An oligosaccharide (oligos is a Greek word that in its plural form means “few”) yields
3–10 monosaccharide units on hydrolysis. Polysaccharides are hydrolyzed to more than
10 monosaccharide units. Cellulose is a polysaccharide molecule that gives thousands of
glucose molecules when completely hydrolyzed.
Over 200 different monosaccharides are known. They can be grouped according
to the number of carbon atoms they contain and whether they are polyhydroxy aldehydes or polyhydroxy ketones. Monosaccharides that are polyhydroxy aldehydes are
called aldoses; those that are polyhydroxy ketones are ketoses. Aldoses and ketoses are
further classified according to the number of carbon atoms in the main chain. Table 25.1
lists the terms applied to monosaccharides having four to eight carbon atoms.
25.2
FISCHER PROJECTIONS AND D–L NOTATION
Stereochemistry is the key to understanding carbohydrate structure, a fact that was clearly
appreciated by the German chemist Emil Fischer. The projection formulas used by
Fischer to represent stereochemistry in chiral molecules are particularly well-suited to
studying carbohydrates. Figure 25.1 illustrates their application to the enantiomers of
glyceraldehyde (2,3-dihydroxypropanal), a fundamental molecule in carbohydrate stereochemistry. When the Fischer projection is oriented as shown in the figure, with the carbon chain vertical and the aldehyde carbon at the top, the C-2 hydroxyl group points to
the right in ()-glyceraldehyde and to the left in ()-glyceraldehyde.
Techniques for determining the absolute configuration of chiral molecules were not
developed until the 1950s, and so it was not possible for Fischer and his contemporaries
to relate the sign of rotation of any substance to its absolute configuration. A system
evolved based on the arbitrary assumption, later shown to be correct, that the enantiomers
of glyceraldehyde have the signs of rotation and absolute configurations shown in Figure 25.1. Two stereochemical descriptors were defined: D and L. The absolute configuration of ()-glyceraldehyde, as depicted in the figure, was said to be D and that of its
enantiomer, ()-glyceraldehyde, L. Compounds that had a spatial arrangement of substituents analogous to D-()- and L-()-glyceraldehyde were said to have the D and L
configurations, respectively.
TABLE 25.1
Back
Adopting the enantiomers of
glyceraldehyde as stereochemical reference compounds originated with
proposals made in 1906 by
M. A. Rosanoff, a chemist at
New York University.
Some Classes of Monosaccharides
Number of
carbon atoms
Aldose
Ketose
Four
Five
Six
Seven
Eight
Aldotetrose
Aldopentose
Aldohexose
Aldoheptose
Aldooctose
Ketotetrose
Ketopentose
Ketohexose
Ketoheptose
Ketooctose
Forward
Fischer determined the structure of glucose in 1900 and
won the Nobel Prize in
chemistry in 1902.
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CHAPTER TWENTY-FIVE
Carbohydrates
CHœO
CHœO
FIGURE 25.1 Threedimensional representations
and Fischer projections of
the enantiomers of glyceraldehyde.
H
OH
C
OH
H
CH2OH
CH2OH
R-(+)-Glyceraldehyde
CHœO
CHœO
HO
H
HO
H
C
CH2OH
CH2OH
S-(–)-Glyceraldehyde
PROBLEM 25.1 Identify each of the following as either D- or L-glyceraldehyde:
(a)
CH2OH
HO
H
CHO
H
(b)
HOCH2
(c)
HOCH2
CHO
OH
CHO
H
OH
SAMPLE SOLUTION (a) Redraw the Fischer projection so as to more clearly show
the true spatial orientation of the groups. Next, reorient the molecule so that its
relationship to the glyceraldehyde enantiomers in Figure 25.1 is apparent.
CH2OH
HO
H
CHO
CH2OH
is equivalent to
HO
C
H
CHO
turn
180°
CHO
H
C
OH
CH2OH
The structure is the same as that of ()-glyceraldehyde in the figure. It is
glyceraldehyde.
D-
Fischer projections and D–L notation have proved to be so helpful in representing
carbohydrate stereochemistry that the chemical and biochemical literature is replete with
their use. To read that literature you need to be acquainted with these devices, as well
as the more modern Cahn–Ingold–Prelog system.
25.3
Molecular models of the
four stereoisomeric aldotetroses
may be viewed on the CD that
accompanies this text.
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THE ALDOTETROSES
Glyceraldehyde can be considered to be the simplest chiral carbohydrate. It is an
aldotriose and, since it contains one stereogenic center, exists in two stereoisomeric
forms: the D and L enantiomers. Moving up the scale in complexity, next come the
aldotetroses. Examination of their structures illustrates the application of the Fischer system to compounds that contain more than one stereogenic center.
The aldotetroses are the four stereoisomers of 2,3,4-trihydroxybutanal. Fischer projections are constructed by orienting the molecule in an eclipsed conformation with the
aldehyde group at what will be the top. The four carbon atoms define the main chain of
the Fischer projection and are arranged vertically. Horizontal bonds are directed outward,
vertical bonds back.
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25.3
H
CHO
The Aldotetroses
OH
CHO
CHO
H
C
OH
H
C
OH
which is
written as
is equivalent to
H
CH2OH
975
OH
H
OH
CH2OH
CH2OH
OH
H
Fischer projection
of a tetrose
Eclipsed conformation
of a tetrose
The particular aldotetrose just shown is called D-erythrose. The prefix D tells us that the
configuration at the highest numbered stereogenic center is analogous to that of D-()glyceraldehyde. Its mirror image is L-erythrose.
1
1
CHO
Highest numbered
stereogenic center
has configuration
analogous to that of
D-glyceraldehyde
H
H
2
3
4
CHO
OH
HO
OH
HO
2
3
CH2OH
4
D-Erythrose
H
H
Highest numbered
stereogenic center
has configuration
analogous to that of
L-glyceraldehyde
For a first-person account of
the development of systematic carbohydrate nomenclature see C. D. Hurd’s article
in the December 1989 issue
of the Journal of Chemical
Education, pp. 984–988.
CH2OH
L-Erythrose
Relative to each other, both hydroxyl groups are on the same side in Fischer projections of the erythrose enantiomers. The remaining two stereoisomers have hydroxyl
groups on opposite sides in their Fischer projection. They are diastereomers of D- and
L-erythrose and are called D- and L-threose. The D and L prefixes again specify the configuration of the highest numbered stereogenic center. D-Threose and L-threose are enantiomers of each other:
1
1
CHO
Highest numbered
stereogenic center
has configuration
analogous to that of
D-glyceraldehyde
HO
H
2
H
H
3
4
CHO
HO
OH
CH2OH
2
3
4
D-Threose
OH
H
Highest numbered
stereogenic center
has configuration
analogous to that of
L-glyceraldehyde
CH2OH
L-Threose
PROBLEM 25.2 Which aldotetrose is the structure shown? Is it D-erythrose,
D-threose, L-erythrose, or L-threose? (Be careful! The conformation given is not
the same as that used to generate a Fischer projection.)
2
4
3
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CHAPTER TWENTY-FIVE
Carbohydrates
As shown for the aldotetroses, an aldose belongs to the D or the L series according to the configuration of the stereogenic center farthest removed from the aldehyde
function. Individual names, such as erythrose and threose, specify the particular arrangement of stereogenic centers within the molecule relative to each other. Optical activities
cannot be determined directly from the D and L prefixes. As it turns out, both D-erythrose
and D-threose are levorotatory, but D-glyceraldehyde is dextrorotatory.
25.4
ALDOPENTOSES AND ALDOHEXOSES
Aldopentoses have three stereogenic centers. The eight stereoisomers are divided into a
set of four D-aldopentoses and an enantiomeric set of four L-aldopentoses. The aldopentoses are named ribose, arabinose, xylose, and lyxose. Fischer projections of the D
stereoisomers of the aldopentoses are given in Figure 25.2. Notice that all these diastereomers have the same configuration at C-4 and that this configuration is analogous to that
of D-()-glyceraldehyde.
PROBLEM 25.3 L-()-Arabinose is a naturally occurring L sugar. It is obtained by
acid hydrolysis of the polysaccharide present in mesquite gum. Write a Fischer projection for L-()-arabinose.
Cellulose is more abundant
than glucose, but each cellulose molecule is a polysaccharide composed of
thousands of glucose units
(Section 25.15). Methane
may also be more abundant,
but most of the methane
comes from glucose.
Among the aldopentoses, D-ribose is a component of many biologically important
substances, most notably the ribonucleic acids, and D-xylose is very abundant and is isolated by hydrolysis of the polysaccharides present in corncobs and the wood of trees.
The aldohexoses include some of the most familiar of the monosaccharides, as well
as one of the most abundant organic compounds on earth, D-()-glucose. With four
stereogenic centers, 16 stereoisomeric aldohexoses are possible; 8 belong to the D series
and 8 to the L series. All are known, either as naturally occurring substances or as the
products of synthesis. The eight D-aldohexoses are given in Figure 25.2; it is the spatial
arrangement at C-5, hydrogen to the left in a Fischer projection and hydroxyl to the right,
that identifies them as carbohydrates of the D series.
PROBLEM 25.4 Name the following sugar:
CHO
H
OH
H
OH
H
OH
HO
H
CH2OH
Of all the monosaccharides, D-()-glucose is the best known, most important, and
most abundant. Its formation from carbon dioxide, water, and sunlight is the central
theme of photosynthesis. Carbohydrate formation by photosynthesis is estimated to be
on the order of 1011 tons per year, a source of stored energy utilized, directly or indirectly, by all higher forms of life on the planet. Glucose was isolated from raisins in
1747 and by hydrolysis of starch in 1811. Its structure was determined, in work culminating in 1900, by Emil Fischer.
D-()-Galactose is a constituent of numerous polysaccharides. It is best obtained
by acid hydrolysis of lactose (milk sugar), a disaccharide of D-glucose and D-galactose.
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CHO
H
OH
CH2OH
D-()-Glyceraldehyde
CHO
H
H
OH
OH
CHO
HO
H
CH2OH
D-()-Erythrose
CHO
OH
OH
OH
H
H
H
H
CHO
OH
OH
OH
OH
CH2OH
D-()-Allose
HO
H
H
H
H
OH
OH
OH
CH2OH
D-()-Altrose
OH
H
OH
OH
CH2OH
D-()-Glucose
H
HO
H
CH2OH
D-()-Arabinose
CHO
H
HO
H
H
H
OH
OH
HO
H
H
H
H
OH
OH
CH2OH
D-()-Mannose
OH
H
OH
HO
HO
H
CH2OH
D-()-Lyxose
CHO
CHO
H
H
HO
H
OH
OH
H
OH
H
H
OH
CH2OH
D-()-Xylose
CHO
HO
HO
H
H
CHO
CHO
HO
H
HO
H
CH2OH
D-()-Gulose
H
OH
H
OH
CHO
H
HO
HO
H
CH2OH
D-()-Idose
OH
H
H
OH
CH2OH
D-()-Galactose
CHO
HO
HO
HO
H
H
H
H
OH
CH2OH
D-()-Talose
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FIGURE 25.2 Configurations of the D
series of aldoses
containing
three
through six carbon
atoms.
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Aldopentoses and Aldohexoses
CHO
D-()-Threose
CHO
CH2OH
D-()-Ribose
CH2OH
25.4
H
H
H
H
OH
978
CHAPTER TWENTY-FIVE
Carbohydrates
L()-Galactose
also occurs naturally and can be prepared by hydrolysis of flaxseed gum
and agar. The principal source of D-()-mannose is hydrolysis of the polysaccharide of
the ivory nut, a large, nut-like seed obtained from a South American palm.
25.5
See, for example, the November 1955 issue of the
Journal of Chemical Education (p. 584). An article giving references to a variety of
chemistry mnemonics appears in the July 1960 issue
of the Journal of Chemical
Education (p. 366).
A MNEMONIC FOR CARBOHYDRATE CONFIGURATIONS
The task of relating carbohydrate configurations to names requires either a world-class
memory or an easily recalled mnemonic. A mnemonic that serves us well here was popularized by the husband–wife team of Louis F. Fieser and Mary Fieser of Harvard University in their 1956 textbook, Organic Chemistry. As with many mnemonics, it’s not
clear who actually invented it, and references to this particular one appeared in the chemical education literature before publication of the Fiesers’ text. The mnemonic has two
features: (1) a system for setting down all the stereoisomeric D-aldohexoses in a logical
order; and (2) a way to assign the correct name to each one.
A systematic way to set down all the D-hexoses (as in Fig. 25.2) is to draw skeletons of the necessary eight Fischer projections, placing the hydroxyl group at C-5 to the
right in each so as to guarantee that they all belong to the D series. Working up the carbon chain, place the hydroxyl group at C-4 to the right in the first four structures, and
to the left in the next four. In each of these two sets of four, place the C-3 hydroxyl
group to the right in the first two and to the left in the next two; in each of the resulting four sets of two, place the C-2 hydroxyl group to the right in the first one and to the
left in the second.
Once the eight Fischer projections have been written, they are named in order with
the aid of the sentence: All altruists gladly make gum in gallon tanks. The words of the
sentence stand for allose, altrose, glucose, mannose, gulose, idose, galactose, talose.
An analogous pattern of configurations can be seen in the aldopentoses when they
are arranged in the order ribose, arabinose, xylose, lyxose. (RAXL is an easily remembered nonsense word that gives the correct sequence.) This pattern is discernible even
in the aldotetroses erythrose and threose.
25.6
CYCLIC FORMS OF CARBOHYDRATES: FURANOSE FORMS
Aldoses incorporate two functional groups, CœO and OH, which are capable of reacting with each other. We saw in Section 17.8 that nucleophilic addition of an alcohol
function to a carbonyl group gives a hemiacetal. When the hydroxyl and carbonyl groups
are part of the same molecule, a cyclic hemiacetal results, as illustrated in Figure 25.3.
Cyclic hemiacetal formation is most common when the ring that results is five- or
six-membered. Five-membered cyclic hemiacetals of carbohydrates are called furanose
forms; six-membered ones are called pyranose forms. The ring carbon that is derived
from the carbonyl group, the one that bears two oxygen substituents, is called the
anomeric carbon.
Aldoses exist almost exclusively as their cyclic hemiacetals; very little of the openchain form is present at equilibrium. To understand their structures and chemical reactions, we need to be able to translate Fischer projections of carbohydrates into their cyclic
hemiacetal forms. Consider first cyclic hemiacetal formation in D-erythrose. So as to
visualize furanose ring formation more clearly, redraw the Fischer projection in a form
more suited to cyclization, being careful to maintain the stereochemistry at each stereogenic center.
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25.6
Cyclic Forms of Carbohydrates: Furanose Forms
979
Ring oxygen is
derived from
hydroxyl group.
H
O
O
H
HOCH2CH2CH2CH ≡ CH2
C
4-Hydroxybutanal
CH2 CH2
O
H
O
OH
This carbon was
originally the carbonyl
carbon of the aldehyde.
Ring oxygen is
derived from
hydroxyl group.
H
O
CH2
HOCH2CH2CH2CH2CH ≡ CH2
5-Hydroxypentanal
CH2
O
O H
C
CH2
H
O
OH
This carbon was
originally the carbonyl
carbon of the aldehyde.
FIGURE 25.3 Cyclic hemiacetal formation in 4-hydroxybutanal and 5-hydroxypentanal.
H
1
CHO
2
H
is equivalent to
3
H
4
O
H
OH
CH
4
OH
H H
CH2OH
D-Erythrose
O
1
H
3
2
HO
OH
A molecular model can
help you to visualize this
relationship.
Reoriented eclipsed conformation of
D-erythrose showing C-4
hydroxyl group in position to
add to carbonyl group
Hemiacetal formation between the carbonyl group and the terminal hydroxyl yields the fivemembered furanose ring form. The anomeric carbon becomes a new stereogenic center; its
hydroxyl group can be either cis or trans to the other hydroxyl groups of the molecule.
H
O
H
O
CH
4
H H
H
3
2
HO
OH
D-Erythrose
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OH
O
1
O
H
H
HO
H OH
OH
-D-Erythrofuranose
(hydroxyl group at
anomeric carbon is
down)
TOC
H
HO
H H
OH
-D-Erythrofuranose
(hydroxyl group at
anomeric carbon is
up)
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980
CHAPTER TWENTY-FIVE
Carbohydrates
Structural drawings of carbohydrates of this type are called Haworth formulas,
after the British carbohydrate chemist Sir Walter Norman Haworth (St. Andrew’s University and the University of Birmingham). Early in his career Haworth contributed to
the discovery that sugars exist as cyclic hemiacetals rather than in open-chain forms.
Later he collaborated on an efficient synthesis of vitamin C from carbohydrate precursors. This was the first chemical synthesis of a vitamin and provided an inexpensive route
to its preparation on a commercial scale. Haworth was a corecipient of the Nobel Prize
for chemistry in 1937.
The two stereoisomeric furanose forms of D-erythrose are named -D-erythrofuranose and -D-erythrofuranose. The prefixes and describe relative configuration. The
configuration of the anomeric carbon is when its hydroxyl group is on the same side
of a Fischer projection as the hydroxyl group at the highest numbered stereogenic center. When the hydroxyl groups at the anomeric carbon and the highest numbered stereogenic center are on opposite sides of a Fischer projection, the configuration at the
anomeric carbon is .
Substituents that are to the right in a Fischer projection are “down” in the corresponding Haworth formula.
Generating Haworth formulas to show stereochemistry in furanose forms of higher
aldoses is slightly more complicated and requires an additional operation. Furanose forms
of D-ribose are frequently encountered building blocks in biologically important organic
molecules. They result from hemiacetal formation between the aldehyde group and the
hydroxyl at C-4:
1
CHO
H
H
H
2
5
OH
3
OH
4
CH2OH
H
CH
4
Furanose ring
formation involves
this hydroxyl group
OH
5
HO H
CH2OH
D-Ribose
H
3
2
HO
OH
O
1
Eclipsed conformation of D-ribose
Notice that the eclipsed conformation of D-ribose derived directly from the Fischer projection does not have its C-4 hydroxyl group properly oriented for furanose ring formation. We must redraw it in a conformation that permits the five-membered cyclic hemiacetal to form. This is accomplished by rotation about the C(3)±C(4) bond, taking care
that the configuration at C-4 is not changed.
H
5
Try using a molecular
model to help see this.
CH2OH
H
CH
4
HO H
3
HO
H
O
rotate about
C(3)±C(4)
bond
5
HOCH2 O
CH
4
1
H H
H
2
3
2
OH
HO
OH
O
1
Conformation of D-ribose
suitable for furanose ring
formation
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25.7
Cyclic Forms of Carbohydrates: Pyranose Forms
981
As viewed in the drawing, a 120° anticlockwise rotation of C-4 places its hydroxyl group
in the proper position. At the same time, this rotation moves the CH2OH group to a position such that it will become a substituent that is “up” on the five-membered ring. The
hydrogen at C-4 then will be “down” in the furanose form.
H
5
HOCH2 O
HOCH2 O
CH
4
H H
3
2
HO
OH
HOCH2 O
H
H H
H OH
O
1
H
OH
H H
H H
HO
HO
OH
-D-Ribofuranose
OH
-D-Ribofuranose
PROBLEM 25.5 Write Haworth formulas corresponding to the furanose forms
of each of the following carbohydrates:
(c) L-Arabinose
(a) D-Xylose
(b) D-Arabinose
(d) D-Threose
SAMPLE SOLUTION (a) The Fischer projection of D-xylose is given in Figure 25.2.
CHO
H
HO
H
5
OH
H
H
CH2OH
CH
4
HO OH
OH
3
D-Xylose
O
2
H
CH2OH
1
H
OH
Eclipsed conformation of D-xylose
Carbon-4 of D-xylose must be rotated in an anticlockwise sense in order to bring
its hydroxyl group into the proper orientation for furanose ring formation.
H
5
H
CH2OH
CH
4
HO OH
3
H
H
1
O
rotate about
C(3)±C(4)
bond
5
HOCH2
CH
H OH
2
3
H
OH
HOCH2 O
4
1
H
HOCH2 O
OH
H
O
H OH
H H
H OH
H
OH
H
H OH
2
OH
-D-Xylofuranose
D-Xylose
25.7
O
OH
-D-Xylofuranose
CYCLIC FORMS OF CARBOHYDRATES: PYRANOSE FORMS
During the discussion of hemiacetal formation in D-ribose in the preceding section, you
may have noticed that aldopentoses have the potential of forming a six-membered cyclic
hemiacetal via addition of the C-5 hydroxyl to the carbonyl group. This mode of ring
closure leads to - and -pyranose forms:
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CHAPTER TWENTY-FIVE
Carbohydrates
CHO
5
H
OH
H
OH
H
OH
H
CH2
OH
4
Pyranose ring
formation
involves this
hydroxyl group
CH2OH
HO
H
H
CH
3
2
HO
OH
O
1
Eclipsed conformation of
D-ribose
D-Ribose
O
H
HO
H
H
OH
OH
H
-D-Ribopyranose
O
H
OH
HO
H
H
H
OH
OH
OH
-D-Ribopyranose
Like aldopentoses, aldohexoses such as D-glucose are capable of forming two furanose forms ( and ) and two pyranose forms ( and ). The Haworth representations
of the pyranose forms of D-glucose are constructed as shown in Figure 25.4; each has a
CH2OH group as a substituent on the six-membered ring.
Haworth formulas are satisfactory for representing configurational relationships in
pyranose forms but are uninformative as to carbohydrate conformations. X-ray crystallographic studies of a large number of carbohydrates reveal that the six-membered pyranose ring of D-glucose adopts a chair conformation:
HOCH2
Make a molecular model
of the chair conformation of
-D-glucopyranose.
O
H
HO
OH
H
H
OH
H
H
H
HOCH2
HO
HO
OH
H
OH
O
H
OH
H
-D-Glucopyranose
HOCH2
O
H
HO
OH
H
H
H
OH
H
H
HOCH2
HO
HO
OH
O
H
H
H
OH
OH
-D-Glucopyranose
All the ring substituents other than hydrogen in -D-glucopyranose are equatorial in the
most stable chair conformation. Only the anomeric hydroxyl group is axial in the isomer; all the other substituents are equatorial.
Other aldohexoses behave similarly in adopting chair conformations that permit the
CH2OH substituent to occupy an equatorial orientation. Normally the CH2OH group is the
bulkiest, most conformationally demanding substituent in the pyranose form of a hexose.
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25.7
Cyclic Forms of Carbohydrates: Pyranose Forms
983
1
CHO
H
2
H
HO
H
H
OH
H
OH
OH
3
4
5
5
H
6
CH2OH H
OH
OH
4
HO
C
O
2
3
H
CH2OH
1
H
OH
6
D-Glucose
(hydroxyl group at
C-5 is involved in pyranose
ring formation)
Eclipsed conformation of D-Glucose;
hydroxyl at C-5 is not properly
oriented for ring formation
rotate about C-4–C-5
bond in anticlockwise
direction
6
HOCH2
HOCH2
O
H
H
OH
HO
OH
O
H
H
OH
H
H
HO
5
H
H
4
H
HO
OH
H
OH
3
H
OH
H
-D-Glucopyranose
H
HOCH2
H
OH
-D-Glucopyranose
H
O
C
H
1
O
2
OH
Eclipsed conformation of D-glucose in
proper orientation for pyranose
ring formation
PROBLEM 25.6 Clearly represent the most stable conformation of the -pyranose form of each of the following sugars:
(c) L-Mannose
(a) D-Galactose
(b) D-Mannose
(d) L-Ribose
FIGURE 25.4 Haworth formulas for - and -pyranose
forms of D-glucose.
SAMPLE SOLUTION (a) By analogy with the procedure outlined for D-glucose in
Figure 25.4, first generate a Haworth formula for -D-galactopyranose:
CHO
H
HO
H
HO
H
H
H
OH
HO
OH
H
HOCH2
CH2OH
O
HO
OH
OH
H
H
OH
CH
O
H
OH
OH
H
H
OH
H
CH2OH
-D-Galactopyranose
(Haworth formula)
D-Galactose
Next, redraw the planar Haworth formula more realistically as a chair conformation, choosing the one that has the CH2OH group equatorial.
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CHAPTER TWENTY-FIVE
HOCH2
O
HO
H
OH
H
H
Carbohydrates
HO
H
HOCH2
OH
H
HO
H
rather than
H
H
OH
H
OH
HO
OH
H
OH
O
HOCH2
OH
H
O
H
H
H
Most stable chair
conformation of
-D-galactopyranose
OH
Less stable chair;
CH2OH group is axial
Galactose differs from glucose in configuration at C-4. The C-4 hydroxyl is axial in
-D-galactopyranose, but it is equatorial in -D-glucopyranose.
Since six-membered rings are normally less strained than five-membered ones,
pyranose forms are usually present in greater amounts than furanose forms at equilibrium, and the concentration of the open-chain form is quite small. The distribution of
carbohydrates among their various hemiacetal forms has been examined by using 1H and
13
C NMR spectroscopy. In aqueous solution, for example, D-ribose is found to contain
the various and -furanose and pyranose forms in the amounts shown in Figure 25.5.
The concentration of the open-chain form at equilibrium is too small to measure directly.
Nevertheless, it occupies a central position, in that interconversions of and anomers
and furanose and pyranose forms take place by way of the open-chain form as an intermediate. As will be seen later, certain chemical reactions also proceed by way of the
open-chain form.
H
H
H
HO
HOCH2
O
H
OH
H
HO H
H
H
OH
H
H
OH
H
-D-Ribopyranose (56%)
OH
O
C
H
H
H
O
OH
-D-Ribofuranose (18%)
OH
OH
OH
CH2OH
H
H
HO
FIGURE 25.5 Distribution of
furanose, pyranose, and
open-chain forms of D-ribose
in aqueous solution as measured by 1H and 13C NMR
spectroscopy.
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Open-chain form
of D-ribose
(less than 1%)
H
H
HO H
O
H
OH
OH
-D-Ribopyranose (20%)
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HOCH2
H
O
H
H
OH
H
OH
OH
-D-Ribofuranose (6%)
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25.8
25.8
Mutarotation
985
MUTAROTATION
In spite of their easy interconversion in solution, and forms of carbohydrates are
capable of independent existence, and many have been isolated in pure form as crystalline solids. When crystallized from ethanol, D-glucose yields -D-glucopyranose, mp
146°C, []D 112.2°. Crystallization from a water–ethanol mixture produces -Dglucopyranose, mp 148–155°C, []D 18.7°. In the solid state the two forms do not
interconvert and are stable indefinitely. Their structures have been unambiguously confirmed by X-ray crystallography.
The optical rotations just cited for each isomer are those measured immediately
after each one is dissolved in water. On standing, the rotation of the solution containing
the isomer decreases from 112.2° to 52.5°; the rotation of the solution of the
isomer increases from 18.7° to the same value of 52.5°. This phenomenon is called
mutarotation. What is happening is that each solution, initially containing only one
anomeric form, undergoes equilibration to the same mixture of - and -pyranose forms.
The open-chain form is an intermediate in the process.
HOCH2
HO
HO
HOCH2
O
HO
HO
OH
OH
OH
-D-Glucopyranose
(mp 146°C;
[]D 112.2°)
HOCH2
OH
CHœO
Open-chain form
of D-glucose
HO
HO
O
OH
OH
-D-Glucopyranose
(mp 148–155°C;
[]D 18.7°)
The distribution between the and anomeric forms at equilibrium is readily calculated from the optical rotations of the pure isomers and the final optical rotation of the
solution, and is determined to be 36% to 64% . Independent measurements have
established that only the pyranose forms of D-glucose are present in significant quantities at equilibrium.
PROBLEM 25.7 The specific optical rotations of pure - and -D-mannopyranose
are 29.3° and 17.0°, respectively. When either form is dissolved in water,
mutarotation occurs, and the observed rotation of the solution changes until a
final rotation of 14.2° is observed. Assuming that only - and -pyranose forms
are present, calculate the percent of each isomer at equilibrium.
It’s not possible to tell by inspection whether the - or -pyranose form of a
particular carbohydrate predominates at equilibrium. As just described, the -pyranose
form is the major species present in an aqueous solution of D-glucose, whereas the
-pyranose form predominates in a solution of D-mannose (Problem 25.7). The relative
abundance of -and -pyranose forms in solution is a complicated issue and depends on
several factors. One is solvation of the anomeric hydroxyl group. An equatorial OH is
less crowded and better solvated by water than an axial one. This effect stabilizes the
-pyranose form in aqueous solution. A second factor, called the anomeric effect,
involves an electronic interaction between the ring oxygen and the anomeric substituent
and preferentially stabilizes the axial OH of the -pyranose form. Because the two effects
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A 13C NMR study of Dglucose in water detected
five species: the -pyranose
(38.8%), -pyranose (60.9%),
-furanose (0.14%), and
-furanose (0.15%) forms,
and the hydrate of the openchain form (0.0045%).
The anomeric effect is best
explained by a molecular orbital analysis that is beyond
the scope of this text.
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986
CHAPTER TWENTY-FIVE
Carbohydrates
operate in different directions but are comparable in magnitude in aqueous solution, the
-pyranose form is more abundant for some carbohydrates and the -pyranose form for
others.
25.9
KETOSES
Up to this point all our attention has been directed toward aldoses, carbohydrates having an aldehyde function in their open-chain form. Aldoses are more common than
ketoses, and their role in biological processes has been more thoroughly studied. Nevertheless, a large number of ketoses are known, and several of them are pivotal intermediates in carbohydrate biosynthesis and metabolism. Examples of some ketoses
include D-ribulose, L-xylulose, and D-fructose:
CH2OH
CH2OH
CH2OH
C
C
C
O
H
OH
H
H
OH
HO
O
OH
HO
H
CH2OH
O
CH2OH
H
H
OH
H
OH
CH2OH
D-Ribulose
(a 2-ketopentose
that is a key
compound in
photosynthesis)
L-Xylulose
(a 2-ketopentose
excreted in excessive
amounts in the urine
of persons afflicted
with the mild genetic
disorder pentosuria)
D-Fructose
(a 2-ketohexose also
known as levulose;
it is found in honey
and is signficantly
sweeter than table
sugar)
In these three examples the carbonyl group is located at C-2, which is the most common location for the carbonyl function in naturally occurring ketoses.
PROBLEM 25.8 How many ketotetroses are possible? Write Fischer projections
for each.
Ketoses, like aldoses, exist mainly as cyclic hemiacetals. In the case of D-ribulose,
furanose forms result from addition of the C-5 hydroxyl to the carbonyl group.
H
H
O
O
CH2OH
HO
H
O
OH
Eclipsed conformation of
D-ribulose
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CH2OH
C
H H
O
OH
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H
HO
H CH OH
2
OH
-D-Ribulofuranose
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H
HO
H OH
OH
-D-Ribulofuranose
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25.10
Deoxy Sugars
987
The anomeric carbon of a furanose or pyranose form of a ketose bears both a hydroxyl
group and a carbon substituent. In the case of 2-ketoses, this substituent is a CH2OH
group. As with aldoses, the anomeric carbon of a cyclic hemiacetal is readily identifiable because it is bonded to two oxygens.
25.10 DEOXY SUGARS
A commonplace variation on the general pattern seen in carbohydrate structure is the
replacement of one or more of the hydroxyl substituents by some other atom or group.
In deoxy sugars the hydroxyl group is replaced by hydrogen. Two examples of deoxy
sugars are 2-deoxy-D-ribose and L-rhamnose:
CHO
CHO
H
H
H
OH
H
OH
H
OH
H
OH
HO
H
CH2OH
HO
H
CH3
2-Deoxy-D-ribose
L-Rhamnose
(6-deoxy-L-mannose)
The hydroxyl at C-2 in D-ribose is absent in 2-deoxy-D-ribose. In Chapter 27 we shall
see how derivatives of 2-deoxy-D-ribose, called deoxyribonucleotides, are the fundamental building blocks of deoxyribonucleic acid (DNA), the material responsible for storing genetic information. L-Rhamnose is a compound isolated from a number of plants.
Its carbon chain terminates in a methyl rather than a CH2OH group.
PROBLEM 25.9 Write Fischer projections of
(a) Cordycepose (3-deoxy-D-ribose): a deoxy sugar isolated by hydrolysis of the
antibiotic substance cordycepin
(b) L-Fucose (6-deoxy-L-galactose): obtained from seaweed
SAMPLE SOLUTION (a) The hydroxyl group at C-3 in
hydrogen in 3-deoxy-D-ribose.
CHO
H
OH
H
OH
H
OH
H
H
H
OH
H
OH
D-Ribose
(from Figure 25.2)
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is replaced by
CHO
CH2OH
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D-ribose
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CH2OH
3-Deoxy-D-ribose
(cordycepose)
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CHAPTER TWENTY-FIVE
Carbohydrates
25.11 AMINO SUGARS
For a review of the isolation
of chitin from natural
sources and some of its uses,
see the November 1990 issue
of the Journal of Chemical
Education (pp. 938–942).
Another structural variation is the replacement of a hydroxyl group in a carbohydrate by
an amino group to give an amino sugar. The most abundant amino sugar is one of the
oldest and most abundant organic compounds on earth. N-Acetyl-D-glucosamine is the
main component of the polysaccharide in chitin, the substance that makes up the tough
outer skeleton of arthropods and insects. Chitin has been isolated from a 25-million-yearold beetle fossil, and more than 1011 tons of chitin is produced in the biosphere each
year. Lobster shells, for example, are mainly chitin. More than 60 amino sugars are
known, many of them having been isolated and identified only recently as components
of antibiotics. The anticancer drug doxorubicin hydrochloride (Adriamycin), for example, contains the amino sugar L-daunosamine as one of its structural units.
HOCH2
HO
HO
OH
O
OH
HNCCH3
X
O
H3C
H
O
NH2
HO
N-Acetyl-D-glucosamine
L-Daunosamine
25.12 BRANCHED-CHAIN CARBOHYDRATES
Carbohydrates that have a carbon substituent attached to the main chain are said to have
a branched chain. D-Apiose and L-vancosamine are representative branched-chain
carbohydrates:
CHO
CH3
OH
H
HO
CH2OH
Branching
group
H3C
O
HO
CH2OH
D-Apiose
OH
H
NH2
L-Vancosamine
D-Apiose
can be isolated from parsley and is a component of the cell wall polysaccharide of various marine plants. Among its novel structural features is the presence of only
a single stereogenic center. L-Vancosamine is but one portion of vancomycin, a powerful
antibiotic that is reserved for treating only the most stubborn infections. L-Vancosamine
is not only a branched-chain carbohydrate, it is a deoxy sugar and an amino sugar as well.
25.13 GLYCOSIDES
Glycosides are a large and very important class of carbohydrate derivatives characterized by the replacement of the anomeric hydroxyl group by some other substituent. Glycosides are termed O-glycosides, N-glycosides, S-glycosides, and so on, according to the
atom attached to the anomeric carbon.
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25.13
Glycosides
989
NH2
N
N
N
N
HOCH2 O
HOCH2
O
HO
HO
OH
HOCH2
CH3
W
OC±CPN
W
CH3
H H
HO
HO
H H
O
OH
HO
OH
Adenosine
(an N-glycoside: also
known as a nucleoside;
adenosine is one of the
fundamental molecules
of biochemistry)
Linamarin
(an O-glycoside:
obtained from manioc,
a type of yam widely
distributed in
southeast Asia)
NOSO2K
X
SCCH2CHœCH2
Sinigrin
(an S-glycoside:
contributes to the
characteristic flavor
of mustard and
horseradish)
Usually, the term “glycoside” without a prefix is taken to mean an O-glycoside and will
be used that way in this chapter. Glycosides are classified as or in the customary
way, according to the configuration at the anomeric carbon. All three of the glycosides
just shown are -glycosides. Linamarin and sinigrin are glycosides of D-glucose; adenosine is a glycoside of D-ribose.
Structurally, O-glycosides are mixed acetals that involve the anomeric position of
furanose and pyranose forms of carbohydrates. Recall the sequence of intermediates in
acetal formation (Section 17.8):
R2C
O
ROH
Aldehyde or
ketone
ROH
R2COR
R2COR
OH
OR
Hemiacetal
Acetal
When this sequence is applied to carbohydrates, the first step takes place intramolecularly and spontaneously to yield a cyclic hemiacetal. The second step is intermolecular,
requires an alcohol ROH as a reactant, and proceeds readily only in the presence of an
acid catalyst. An oxygen-stabilized carbocation is an intermediate.
R2COR
OH
H
H
R2COR
H2O
H2O
R2C
ROH
OR
ROH
HOH
HOR
Hemiacetal
R2COR
Oxygen-stabilized
carbocation
H
H
R2COR
OR
Mixed
acetal
The preparation of glycosides in the laboratory is carried out by simply allowing
a carbohydrate to react with an alcohol in the presence of an acid catalyst:
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CHAPTER TWENTY-FIVE
Carbohydrates
CHO
OH
H
HO
H
H
OH
H
CH3OH
HOCH2
HCl
HOCH2
O
HO
HO
OH
OH
O
HO
HO
OCH3
OH
OCH3
CH2OH
D-Glucose
Methanol
Methyl
-D-glucopyranoside
(major product; isolated
in 49% yield)
Methyl
-D-glucopyranoside
(minor product)
PROBLEM 25.10 Write structural formulas for the - and -methyl pyranosides
formed by reaction of D-galactose with methanol in the presence of hydrogen
chloride.
A point to be emphasized about glycoside formation is that, despite the presence
of a number of other hydroxyl groups in the carbohydrate, only the anomeric hydroxyl
group is replaced. This is because a carbocation at the anomeric position is stabilized
by the ring oxygen and is the only one capable of being formed under the reaction conditions.
HOCH2
O
HO
HO
H
OH
H2O
HOCH2
HOCH2
O
HO
HO
OH
OH
D-Glucose
(shown in -pyranose form)
OH
H
H
O
HO
HO
H
Electron pair on ring oxygen can stabilize
carbocation at anomeric position only.
Once the carbocation is formed, it is captured by the alcohol acting as a nucleophile.
Attack can occur at either the or face of the carbocation.
Attack at the face gives methyl -D-glucopyranoside:
HOCH2
HOCH2
CH3
O
HO
HO
HO
HO
O
OH
H
H
O
H
H
H
OH
H
HOCH2
HO
HO
O
H
OH
O
OCH3
CH3
Methyl -D-glucopyranoside
Carbocation intermediate Methanol
Attack at the face gives methyl -D-glucopyranoside:
HOCH2
HO
HO
CH3
O
O
OH
H
H
HOCH2
HO
HO
O
CH3
O
OH
H
H
H
Carbocation intermediate Methanol
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H
HOCH2
O
HO
HO
OH
OCH3
H
Methyl -D-glucopyranoside
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25.14
Disaccharides
991
All of the reactions, from D-glucose to the methyl glycosides via the carbocation,
are reversible. The overall reaction is thermodynamically controlled and gives the same
mixture of glycosides irrespective of which stereoisomeric pyranose form of D-glucose
we start with. Nor does it matter whether we start with a pyranose form or a furanose
form of D-glucose. Glucopyranosides are more stable than glucofuranosides and predominate at equilibrium.
PROBLEM 25.11 Methyl glycosides of 2-deoxy sugars have been prepared by the
acid-catalyzed addition of methanol to unsaturated sugars known as glycals.
HO
HOCH2
HO
HOCH2
O
HO
CH3OH
HCl
H
HO
HOCH2
O
HO
H
HO
OCH3
H
OCH3
Galactal
O
Methyl 2-deoxy--Dlyxohexopyranoside
(38%)
Methyl 2-deoxy--Dlyxohexopyranoside
(36%)
Suggest a reasonable mechanism for this reaction.
Under neutral or basic conditions glycosides are configurationally stable; unlike
the free sugars from which they are derived, glycosides do not exhibit mutarotation. Converting the anomeric hydroxyl group to an ether function (hemiacetal → acetal) prevents
its reversion to the open-chain form in neutral or basic media. In aqueous acid, acetal
formation can be reversed and the glycoside hydrolyzed to an alcohol and the free sugar.
25.14 DISACCHARIDES
Disaccharides are carbohydrates that yield two monosaccharide molecules on hydrolysis. Structurally, disaccharides are glycosides in which the alkoxy group attached to the
anomeric carbon is derived from a second sugar molecule.
Maltose, obtained by the hydrolysis of starch, and cellobiose, by the hydrolysis of
cellulose, are isomeric disaccharides. In both maltose and cellobiose two D-glucopyranose units are joined by a glycosidic bond between C-1 of one unit and C-4 of the other.
The two are diastereomers, differing only in the stereochemistry at the anomeric carbon
of the glycoside bond; maltose is an -glycoside, cellobiose is a -glycoside.
HOCH2
HOCH2
O
HO
O
O
1
HO
OH
Maltose:
OH
4
HO
You can view molecular
models of maltose and cellobiose on Learning By Modeling.
()
Cellobiose: ()
OH
The stereochemistry and points of connection of glycosidic bonds are commonly
designated by symbols such as (1,4) for maltose and (1,4) for cellobiose; and designate the stereochemistry at the anomeric position; the numerals specify the ring carbons involved.
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CHAPTER TWENTY-FIVE
Carbohydrates
Both maltose and cellobiose have a free anomeric hydroxyl group that is not
involved in a glycoside bond. The configuration at the free anomeric center is variable
and may be either or . Indeed, two stereoisomeric forms of maltose have been isolated: one has its anomeric hydroxyl group in an equatorial orientation; the other has an
axial anomeric hydroxyl.
The free anomeric hydroxyl
group is the one shown at
the far right of the preceding
structural formula. The symbol UU is used to represent
a bond of variable stereochemistry.
PROBLEM 25.12 The two stereoisomeric forms of maltose just mentioned
undergo mutarotation when dissolved in water. What is the structure of the key
intermediate in this process?
The single difference in their structures, the stereochemistry of the glycosidic bond,
causes maltose and cellobiose to differ significantly in their three-dimensional shape, as
the molecular models of Figure 25.6 illustrate. This difference in shape affects the way
in which maltose and cellobiose interact with other chiral molecules such as proteins,
and they behave much differently toward enzyme-catalyzed hydrolysis. An enzyme
known as maltase catalyzes the hydrolytic cleavage of the -glycosidic bond of maltose
but is without effect in promoting the hydrolysis of the -glycosidic bond of cellobiose.
A different enzyme, emulsin, produces the opposite result: emulsin catalyzes the hydrolysis of cellobiose but not of maltose. The behavior of each enzyme is general for glucosides (glycosides of glucose). Maltase catalyzes the hydrolysis of -glucosides and is
1
4
Maltose
FIGURE 25.6 Molecular models of the disaccharides maltose and cellobiose.
Two D-glucopyranose units
are connected by a glycoside
linkage between C-1 and C-4.
The glycosidic bond has the orientation in maltose and is
in cellobiose. Maltose and
cellobiose are diastereomers.
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1
4
Cellobiose
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25.15
portion
of molecule
Polysaccharides
993
D-Glucose
FIGURE 25.7
structure of sucrose.
D-Fructose
portion
of molecule
HOCH2
O
HO
HO
H
HO
OH
The
OH
CH2OH
O
O
-Glycoside bond
to anomeric position
CH2OH
of D-glucose
-Glycoside
bond to anomeric
position of
D-fructose
also known as -glucosidase, whereas emulsin catalyzes the hydrolysis of -glucosides
and is known as -glucosidase. The specificity of these enzymes offers a useful tool for
structure determination because it allows the stereochemistry of glycosidic linkages to
be assigned.
Lactose is a disaccharide constituting 2–6% of milk and is known as milk sugar.
It differs from maltose and cellobiose in that only one of its monosaccharide units is
D-glucose. The other monosaccharide unit, the one that contributes its anomeric carbon
to the glycoside bond, is D-galactose. Like cellobiose, lactose is a -glycoside.
HOCH2
O
Cellobiose:
Lactose:
HOCH2
HO
1
HO
O
O
OH HO
You can view molecular
models of cellobiose and lactose
on Learning By Modeling.
OH
4
OH
Digestion of lactose is facilitated by the -glycosidase lactase. A deficiency of this
enzyme makes it difficult to digest lactose and causes abdominal discomfort. Lactose
intolerance is a genetic trait; it is treatable through over-the-counter formulations of lactase and by limiting the amount of milk in the diet.
The most familiar of all the carbohydrates is sucrose—common table sugar.
Sucrose is a disaccharide in which D-glucose and D-fructose are joined at their anomeric
carbons by a glycosidic bond (Figure 25.7). Its chemical composition is the same
irrespective of its source; sucrose from cane and sucrose from sugar beets are chemically identical. Since sucrose does not have a free anomeric hydroxyl group, it does not
undergo mutarotation.
25.15 POLYSACCHARIDES
Cellulose is the principal structural component of vegetable matter. Wood is 30–40% cellulose, cotton over 90%. Photosynthesis in plants is responsible for the formation of 109
tons per year of cellulose. Structurally, cellulose is a polysaccharide composed of several thousand D-glucose units joined by (1,4)-glycosidic linkages (Figure 25.8). Complete hydrolysis of all the glycosidic bonds of cellulose yields D-glucose. The disaccharide fraction that results from partial hydrolysis is cellobiose.
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CHAPTER TWENTY-FIVE
Carbohydrates
6
FIGURE 25.8 Cellulose is a polysaccharide in
which D-glucose units are
connected by (1,4)-glycoside linkages analogous to
cellobiose. Hydrogen bonding, especially between the
C-2 and C-6 hydroxyl groups,
causes adjacent glucose units
to be turned at an angle of
180° with each other.
FIGURE 25.9 Amylose is a
polysaccharide in which Dglucose units are connected
by (1,4)-glycoside linkages
analogous to maltose.
2
2
1
4
1
4
4
1
1
4
2
2
6
6
Animals lack the enzymes necessary to catalyze the hydrolysis of cellulose and so
can’t digest it. Cattle and other ruminants use cellulose as a food source in an indirect
way. Colonies of microorganisms that live in their digestive tract consume cellulose and
in the process convert it to other substances that the animal can digest.
A more direct source of energy for animals is provided by the starches found in
many foods. Starch is a mixture of a water-dispersible fraction called amylose and a second component, amylopectin. Amylose is a polysaccharide made up of about 100 to several thousand D-glucose units joined by (1,4)-glycosidic bonds (Figure 25.9).
Like amylose, amylopectin is a polysaccharide of (1,4)-linked D-glucose units.
Instead of being a continuous length of (1,4) units, however, amylopectin is branched.
Attached to C-6 at various points on the main chain are short polysaccharide branches
of 24–30 glucose units joined by (1,4)-glycosidic bonds.
HO
O
O
O
O
O
HO
O
HO
O
O
HO
O
HO
HO
O
HO
O
O
HO
O
O
O
O
O
O
HO
O
O
OH
O
HO
O
O
O
OH
O
O
O
O
O
O
OH
O
HO
O
OH
O
O
O
O
O
OH
O
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25.16
Cell-Surface Glycoproteins
995
Starch is a plant’s way of storing glucose to meet its energy needs. Animals can
tap that source by eating starchy foods and, with the aid of their -glycosidase enzymes,
hydrolyze the starch to glucose. When more glucose is available than is needed as fuel,
animals store it as glycogen. Glycogen is similar to amylopectin in that it is a branched
polysaccharide of (1,4)-linked D-glucose units with subunits connected to C-6 of the
main chain.
25.16 CELL-SURFACE GLYCOPROTEINS
That carbohydrates play an informational role in biological interactions is a recent revelation of great importance. Glycoproteins, protein molecules covalently bound to carbohydrates, are often the principal species involved. When a cell is attacked by a virus
or bacterium or when it interacts with another cell, the drama begins when the foreign
particle attaches itself to the surface of the host cell. The invader recognizes the host by
the glycoproteins on the cell surface. More specifically, it recognizes particular carbohydrate sequences at the end of the glycoprotein. For example, the receptor on the cell
surface to which an influenza virus attaches itself has been identified as a glycoprotein
terminating in a disaccharide of N-acetylgalactosamine and N-acetylneuraminic acid
(Figure 25.10). Since attachment of the invader to the surface of the host cell is the first
step in infection, one approach to disease prevention is to selectively inhibit this
“host–guest” interaction. Identifying the precise nature of the interaction is the first step
in the rational design of drugs that prevent it.
Human blood group substances offer another example of the informational role
played by carbohydrates. The structure of the glycoproteins attached to the surface of
blood cells determines whether blood is type A, B, AB, or O. Differences between the
carbohydrate components of the various glycoproteins have been identified and are
shown in Figure 25.11. Compatibility of blood types is dictated by antigen–antibody
interactions. The cell-surface glycoproteins are antigens. Antibodies present in certain
blood types can cause the blood cells of certain other types to clump together, and thus
set practical limitations on transfusion procedures. The antibodies “recognize” the antigens they act on by their terminal saccharide units.
Antigen–antibody interactions are the fundamental basis by which the immune system functions. These interactions are chemical in nature and often involve associations
between glycoproteins of an antigen and complementary glycoproteins of the antibody.
The precise chemical nature of antigen–antibody association is an area of active investigation, with significant implications for chemistry, biochemistry, and physiology.
N-Acetylgalactosamine
O
X
CH3CNH
N-Acetylneuraminic acid
OH
HO
CO2H
O
OH
CH2O
O
O
HO
PROTEIN
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O
X
NHCCH3
OH
CH2OH
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FIGURE 25.10 Diagram of a
cell-surface
glycoprotein,
showing the disaccharide
unit that is recognized by an
invading influenza virus.
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CHAPTER TWENTY-FIVE
FIGURE 25.11 Terminal carbohydrate units of human
blood-group glycoproteins.
The structural difference
between the type A, type B,
and type O glycoproteins lies
in the group designated R.
HO
Carbohydrates
CH2OH
O
N-Acetylgalactosamine
±
O±
Polymer
R±O
Protein
O
H3C
O
OH
HO
HO
HO
HO
CH2OH
CH2OH
O
O
HO
HO
H±
OH
CH3CNH
X
O
R
R
R
Type A
Type B
Type O
25.17 CARBOHYDRATE STRUCTURE DETERMINATION
The classical approach to
structure determination in
carbohydrate chemistry is
best exemplified by Fischer’s
work with D-glucose. A detailed account of this study
appears in the August 1941
issue of the Journal of Chemical Education (pp. 353–357).
Present-day techniques for structure determination in carbohydrate chemistry are substantially the same as those for any other type of compound. The full range of modern
instrumental methods, including mass spectrometry and infrared and nuclear magnetic
resonance spectroscopy, is brought to bear on the problem. If the unknown substance is
crystalline, X-ray diffraction can provide precise structural information that in the best
cases is equivalent to taking a three-dimensional photograph of the molecule.
Before the widespread availability of instrumental methods, the major approach to
structure determination relied on a battery of chemical reactions and tests. The response
of an unknown substance to various reagents and procedures provided a body of data
from which the structure could be deduced. Some of these procedures are still used to
supplement the information obtained by instrumental methods. To better understand the
scope and limitations of these tests, a brief survey of the chemical reactions of carbohydrates is in order. In many cases these reactions are simply applications of chemistry
you have already learned. Certain of the transformations, however, are unique to carbohydrates.
25.18 REDUCTION OF CARBOHYDRATES
Although carbohydrates exist almost entirely as cyclic hemiacetals in aqueous solution,
they are in rapid equilibrium with their open-chain forms, and most of the reagents that
react with simple aldehydes and ketones react in an analogous way with the carbonyl
functional groups of carbohydrates.
The carbonyl group of carbohydrates can be reduced to an alcohol function. Typical procedures include catalytic hydrogenation and sodium borohydride reduction. Lithium
aluminum hydride is not suitable, because it is not compatible with the solvents (water,
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25.18
Reduction of Carbohydrates
997
HOW SWEET IT IS!
H
ow sweet is it?
There is no shortage of compounds, natural or synthetic, that taste sweet. The most
familiar are naturally occurring sugars, especially sucrose, glucose, and fructose. All occur naturally, with
worldwide production of sucrose from cane and
sugar beets exceeding 100 million tons per year. Glucose is prepared by the enzymatic hydrolysis of
starch, and fructose is made by the isomerization of
glucose.
CH
H
H
HOCH2
HO
O
H
OH
H
OH
H
OH
H
OH
CH2OH
CH2OH
D-()-Glucose
D-()-Fructose
enhanced sweetness permits less to be used, reducing
the cost of production. Using less carbohydrate-based
sweetener also reduces the number of calories.
Artificial sweeteners are a billion-dollar-peryear industry. The primary goal is, of course, to maximize sweetness and minimize calories. We’ll look at
the following three sweeteners to give us an overview of the field.
O
O
O
HO
H
HO
NH
C
Glucose
isomerase
H
Among sucrose, glucose, and fructose, fructose is the
sweetest. Honey is sweeter than table sugar because
it contains fructose formed by the isomerization of
glucose as shown in the equation.
You may have noticed that most soft drinks contain “high-fructose corn syrup.” Corn starch is hydrolyzed to glucose, which is then treated with glucose isomerase to produce a fructose-rich mixture. The
Cl
CH2OH
OH
HO
Starch H2O
O
OH
OH
O
SO2
O
CH2Cl
Sucralose
All three of these are hundreds of times sweeter than
sucrose and variously described as “low-calorie” or
“nonnutritive” sweeteners.
Saccharin was discovered at Johns Hopkins University in 1879 in the course of research on coal-tar
derivatives and is the oldest artificial sweetener. In
spite of its name, which comes from the Latin word
for sugar, saccharin bears no structural relationship
to any sugar. Nor is saccharin itself very soluble in water. The proton bonded to nitrogen, however, is fairly
acidic and saccharin is normally marketed as its
water-soluble sodium or calcium salt. Its earliest
OCCH2
O
ClCH2
Saccharin
H3NCHCNHCHCH2
COCH3
O
Aspartame
applications were not in weight control, but as a
replacement for sugar in the diet of diabetics before
insulin became widely available.
Sucralose has the structure most similar to sucrose. Galactose replaces the glucose unit of sucrose,
and chlorines replace three of the hydroxyl groups.
Sucralose is the newest artificial sweetener, having
been approved by the U.S. Food and Drug Administration in 1998. The three chlorine substituents do
not diminish sweetness, but do interfere with the
ability of the body to metabolize sucralose. It, therefore, has no food value and is “noncaloric.”
—Cont.
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CHAPTER TWENTY-FIVE
Carbohydrates
Saccharin, sucralose, and aspartame illustrate
the diversity of structural types that taste sweet, and
the vitality and continuing development of the industry of which they are a part.*
Aspartame is the market leader among artificial sweeteners. It is a methyl ester of a dipeptide, unrelated to any carbohydrate. It was discovered in the
course of research directed toward developing drugs
to relieve indigestion.
*For more information, including theories of structure–taste relationships, see the symposium “Sweeteners and Sweetness Theory” in the August, 1995 issue of the Journal of Chemical Education, pp. 671–683.
alcohols) that are required to dissolve carbohydrates. The products of carbohydrate reduction are called alditols. Since these alditols lack a carbonyl group, they are, of course,
incapable of forming cyclic hemiacetals and exist exclusively in noncyclic forms.
CHO
OH
H
-D-Galactofuranose, or
-D-Galactofuranose, or
-D-Galactopyranose, or
-D-Galactopyranose
CH2OH
HO
H
HO
H
H
H
NaBH4
H2O
OH
OH
HO
H
HO
H
H
CH2OH
OH
CH2OH
D-Galactose
D-Galactitol
(90%)
PROBLEM 25.13 Does sodium borohydride reduction of D-ribose yield an optically active product? Explain.
Another name for glucitol, obtained by reduction of D-glucose, is sorbitol; it is
used as a sweetener, especially in special diets required to be low in sugar. Reduction
of D-fructose yields a mixture of glucitol and mannitol, corresponding to the two possible configurations at the newly generated stereogenic center at C-2.
25.19 OXIDATION OF CARBOHYDRATES
A characteristic property of an aldehyde function is its sensitivity to oxidation. A solution of copper(II) sulfate as its citrate complex (Benedict’s reagent) is capable of oxidizing aliphatic aldehydes to the corresponding carboxylic acid.
O
RCH
Aldehyde
Benedict’s reagent is the key
material in a test kit available from drugstores that
permits individuals to monitor the glucose levels in their
urine.
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O
2Cu2
From copper(II)
sulfate
5HO
RCO
Hydroxide
ion
Carboxylate
anion
Cu2O
Copper(I)
oxide
3H2O
Water
The formation of a red precipitate of copper(I) oxide by reduction of Cu(II) is taken as
a positive test for an aldehyde. Carbohydrates that give positive tests with Benedict’s
reagent are termed reducing sugars.
Aldoses are reducing sugars, since they possess an aldehyde function in their openchain form. Ketoses are also reducing sugars. Under the conditions of the test, ketoses
equilibrate with aldoses by way of enediol intermediates, and the aldoses are oxidized
by the reagent.
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25.19
CH2OH
CHOH
CH
C
C
CHOH
O
R
OH
R
Ketose
999
O
Cu2
R
Enediol
Oxidation of Carbohydrates
positive test
(Cu2O formed)
Aldose
The same kind of equilibrium is available to -hydroxy ketones generally; such compounds give a positive test with Benedict’s reagent. Any carbohydrate that contains a
free hemiacetal function is a reducing sugar. The free hemiacetal is in equilibrium with
the open-chain form and through it is susceptible to oxidation. Maltose, for example,
gives a positive test with Benedict’s reagent.
HOCH2
HOCH2
O
HO
O
OH
O
HO
HOCH2
HOCH2
O
OH HO
HO
OH
HO
Maltose
OH
CH
O
OH HO
O
Cu2
positive test
(Cu2O formed)
OH
Open-chain form of maltose
Glycosides, in which the anomeric carbon is part of an acetal function, are not reducing
sugars and do not give a positive test.
HOCH2
HO
HO
HOCH2
HO
HO
O
O
H
OH
OH
H
O
OH
O
OCH3
OH
CH2OH
HOCH2
Methyl -D-glucopyranoside:
not a reducing sugar
Sucrose: not a reducing sugar
PROBLEM 25.14 Which of the following would be expected to give a positive
test with Benedict’s reagent? Why?
(a) D-Galactitol (see structure in margin) (d) D-Fructose
(b) L-Arabinose
(e) Lactose
(c) 1,3-Dihydroxyacetone
(f) Amylose
SAMPLE SOLUTION (a) D-Galactitol lacks an aldehyde, an -hydroxy ketone, or
a hemiacetal function, so cannot be oxidized by Cu2 and will not give a positive
test with Benedict’s reagent.
CH2OH
H
OH
HO
H
HO
H
H
OH
CH2OH
D-Galactitol
Fehling’s solution, a tartrate complex of copper(II) sulfate, has also been used as
a test for reducing sugars.
Derivatives of aldoses in which the terminal aldehyde function is oxidized to a carboxylic acid are called aldonic acids. Aldonic acids are named by replacing the -ose
ending of the aldose by -onic acid. Oxidation of aldoses with bromine is the most commonly used method for the preparation of aldonic acids and involves the furanose or
pyranose form of the carbohydrate.
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CHAPTER TWENTY-FIVE
Carbohydrates
CO2H
HO
HO
O
OH
OH
Br2
H2O
H
O
HO
HO
OH
HO
OH
H
O
H
H
O
HOCH2 O
H OH
OH
H
CH2OH
-D-Xylopyranose
D-Xylonic
H
OH
acid
(90%)
Aldonic acids exist in equilibrium with their five- or six-membered lactones. They can
be isolated as carboxylate salts of their open-chain forms on treatment with base.
The reaction of aldoses with nitric acid leads to the formation of aldaric acids by
oxidation of both the aldehyde and the terminal primary alcohol function to carboxylic
acid groups. Aldaric acids are also known as saccharic acids and are named by substituting -aric acid for the -ose ending of the corresponding carbohydrate.
CHO
CO2H
OH
H
HO
H
H
OH
H
OH
H
HNO3
60°C
HO
H
H
OH
H
OH
CH2OH
D-Glucose
OH
CO2H
D-Glucaric
acid (41%)
Like aldonic acids, aldaric acids exist mainly as lactones.
PROBLEM 25.15 Another hexose gives the same aldaric acid on oxidation as
does D-glucose. Which one?
Uronic acids occupy an oxidation state between aldonic and aldaric acids. They have
an aldehyde function at one end of their carbon chain and a carboxylic acid group at the other.
CHO
H
HO
OH
H
H
OH
H
OH
HO2C
HO
HO
O
OH
OH
H
CO2H
Fischer projection
of D-glucuronic acid
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-Pyranose form of
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25.20
Cyanohydrin Formation and Carbohydrate Chain Extension
1001
Uronic acids are biosynthetic intermediates in various metabolic processes; ascorbic acid
(vitamin C), for example, is biosynthesized by way of glucuronic acid. Many metabolic
waste products are excreted in the urine as their glucuronate salts.
25.20 CYANOHYDRIN FORMATION AND CARBOHYDRATE CHAIN
EXTENSION
The presence of an aldehyde function in their open-chain forms makes aldoses reactive
toward nucleophilic addition of hydrogen cyanide. Addition yields a mixture of diastereomeric cyanohydrins.
CN
CHO
-L-Arabinofuranose, or
-L-Arabinofuranose, or
-L-Arabinopyranose, or
-L-Arabinopyranose
H
OH
HCN
CN
H
OH
H
OH
HO
H
HO
H
HO
H
HO
H
CH2OH
CH2OH
L-Arabinose
L-Mannononitrile
HO
H
H
OH
HO
H
HO
H
CH2OH
L-Glucononitrile
The reaction is used for the chain extension of aldoses in the synthesis of new or unusual
sugars. In this case, the starting material, L-arabinose, is an abundant natural product and
possesses the correct configurations at its three stereogenic centers for elaboration to the
relatively rare L-enantiomers of glucose and mannose. After cyanohydrin formation, the
cyano groups are converted to aldehyde functions by hydrogenation in aqueous solution.
Under these conditions, ±CPN is reduced to ±CHœNH and hydrolyzes rapidly to
±CHœO. Use of a poisoned palladium-on-barium sulfate catalyst prevents further
reduction to the alditols.
CN
CHO
H
OH
H
OH
HO
H
HO
H
H2, H2O
Pd/BaSO4
CH2OH
L-Mannononitrile
H
OH
H
OH
HO
H
HO
H
CH2OH
L-Mannose
(56% yield from
L-arabinose)
(Similarly, L-glucononitrile has been reduced to L-glucose; its yield was 26% from
L-arabinose.)
An older version of this sequence is called the Kiliani-Fischer synthesis. It, too,
proceeds through a cyanohydrin, but it uses a less efficient method for converting the
cyano group to the required aldehyde.
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CHAPTER TWENTY-FIVE
Carbohydrates
25.21 EPIMERIZATION, ISOMERIZATION, AND RETRO-ALDOL
CLEAVAGE REACTIONS OF CARBOHYDRATES
Carbohydrates undergo a number of isomerization and degradation reactions under both
laboratory and physiological conditions. For example, a mixture of glucose, fructose, and
mannose results when any one of them is treated with aqueous base. This reaction can
be understood by examining the consequences of enolization of glucose:
H
HO
CHO
CHOH
C
C
OH
H
HO
HO, H2O
CHO
HO
OH
H
C
HO
HO, H2O
H
H
H
OH
H
OH
H
OH
H
OH
H
OH
H
OH
CH2OH
D-Glucose
(R configuration
at C-2)
CH2OH
CH2OH
Enediol
(C-2 not a stereogenic
center)
D-Mannose
(S configuration
at C-2)
Because the configuration at C-2 is lost on enolization, the enediol intermediate can
revert either to D-glucose or to D-mannose. Two stereoisomers that have multiple stereogenic centers but differ in configuration at only one of them are referred to as epimers.
Glucose and mannose are epimeric at C-2. Under these conditions epimerization occurs
only at C-2 because it alone is to the carbonyl group.
There is another reaction available to the enediol intermediate. Proton transfer from
water to C-1 converts the enediol not to an aldose but to the ketose D-fructose:
See the boxed essay “How
Sweet It Is!” for more on this
process.
D-Glucose
or
D-Mannose
HO, H2O
CHOH
CH2OH
C
C
HO
OH
H
HO, H2O
HO
O
H
H
OH
H
OH
H
OH
H
OH
CH2OH
Enediol
CH2OH
D-Fructose
The isomerization of D-glucose to D-fructose by way of an enediol intermediate is
an important step in glycolysis, a complex process (11 steps) by which an organism converts glucose to chemical energy. The substrate is not glucose itself but its 6-phosphate
ester. The enzyme that catalyzes the isomerization is called phosphoglucose isomerase.
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25.21
Epimerization, Isomerization, and Retro-Aldol Cleavage Reactions of Carbohydrates
H
O
CHO
CHOH
C
COH
OH
HO
(HO)2POCH2
HO
HO
O
OH
OH
D-Glucose
6-phosphate
H
HO
H
H
OH
H
OH
H
OH
H
OH
CH2OP(OH)2
CH2OP(OH)2
O
O
Open-chain form of
6-phosphate
1003
Enediol
D-glucose
CH2OH
C
HO
O
H
H
OH
H
OH
CH2OP(OH)2
O
CH2OP(OH)2
O
CH2OH
H H
HO OH
OH
H
O
Open-chain form of
D-Fructose 6-phosphate
D-Fructose
6-phosphate
Following its formation, D-fructose 6-phosphate is converted to its corresponding
1,6-phosphate diester, which is then cleaved to two 3-carbon fragments under the influence of the enzyme aldolase:
O
O
CH2OP(OH)2
CH2OP(OH)2
C
C
HO
O
H
H
OH
H
OH
O
CH2OH
aldolase
CH
H
C
O
OH
CH2OP(OH)2
CH2OP(OH)2
O
O
D-Fructose
Dihydroxyacetone
phosphate
D-Glyceraldehyde
3-phosphate
1,6-diphosphate
This cleavage is a retro-aldol reaction. It is the reverse of the process by which D-fructose 1,6-diphosphate would be formed by addition of the enolate of dihydroxyacetone
phosphate to D-glyceraldehyde 3-phosphate. The enzyme aldolase catalyzes both the
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CHAPTER TWENTY-FIVE
Carbohydrates
aldol condensation of the two components and, in glycolysis, the retro-aldol cleavage of
D-fructose 1,6-diphosphate.
Further steps in glycolysis use the D-glyceraldehyde 3-phosphate formed in the
aldolase-catalyzed cleavage reaction as a substrate. Its coproduct, dihydroxyacetone
phosphate, is not wasted, however. The enzyme triose phosphate isomerase converts
dihydroxyacetone phosphate to D-glyceraldehyde 3-phosphate, which enters the glycolysis pathway for further transformations.
PROBLEM 25.16 Suggest a reasonable structure for the intermediate in the conversion of dihydroxyacetone phosphate to D-glyceraldehyde 3-phosphate.
Cleavage reactions of carbohydrates also occur on treatment with aqueous base for
prolonged periods as a consequence of base-catalyzed retro-aldol reactions. As pointed
out in Section 18.9, aldol addition is a reversible process, and -hydroxy carbonyl compounds can be cleaved to an enolate and either an aldehyde or a ketone.
25.22 ACYLATION AND ALKYLATION OF HYDROXYL GROUPS IN
CARBOHYDRATES
The alcohol groups of carbohydrates undergo chemical reactions typical of hydroxyl
functions. They are converted to esters by reaction with acyl chlorides and carboxylic
acid anhydrides.
O
O
HOCH2
HO
HO
O O
O
5CH3COCCH3
pyridine
HO
CH3CO
CH3CO
O
OH
CH2OCCH3
O
CH3CO
OCCH3
O
O
-D-Glucopyranose
Acetic
anhydride
1,2,3,4,6-Penta-O-acetyl-D-glucopyranose (88%)
Ethers are formed under conditions of the Williamson ether synthesis. Methyl
ethers of carbohydrates are efficiently prepared by alkylation with methyl iodide in the
presence of silver oxide.
HOCH2
O
HO
HO
4CH3I
Ag2O
CH3OH
HO
OCH3
Methyl -Dglucopyranoside
CH3OCH2
O
CH3O
CH3O
CH3O
OCH3
Methyl
iodide
Methyl 2,3,4,6-tetra-O-methyl-D-glucopyranoside (97%)
This reaction has been used in an imaginative way to determine the ring size of
glycosides. Once all the free hydroxyl groups of a glycoside have been methylated, the
glycoside is subjected to acid-catalyzed hydrolysis. Only the anomeric methoxy group
is hydrolyzed under these conditions—another example of the ease of carbocation formation at the anomeric position.
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25.23
Periodic Acid Oxidation of Carbohydrates
1005
CHO
H
CH3OCH2
O
CH3O
CH3O
CH3O
H2O
H
CH3OCH2
O
CH3O
CH3O
CH3O
CH3O
OH
OCH3
Methyl 2,3,4,6-tetra-O-methyl-D-glucopyranoside
OCH3
H
H
OCH3
H
OH
2,3,4,6-Tetra-O-methylD-glucose
CH2OCH3
Notice that all the hydroxyl groups in the free sugar except C-5 are methylated. Carbon-5 is not
methylated, because it was originally the site of the ring oxygen in the methyl glycoside.
Once the position of the hydroxyl group in the free sugar has been determined, either by
spectroscopy or by converting the sugar to a known compound, the ring size stands revealed.
25.23 PERIODIC ACID OXIDATION OF CARBOHYDRATES
Periodic acid oxidation (Section 15.12) finds extensive use as an analytical method in
carbohydrate chemistry. Structural information is obtained by measuring the number of
equivalents of periodic acid that react with a given compound and by identifying the
reaction products. A vicinal diol consumes one equivalent of periodate and is cleaved to
two carbonyl compounds:
CR2 HIO4
R2C
HO
O R2C
R2C
O HIO3 H2O
OH
Vicinal
diol
Periodic
acid
Two carbonyl compounds
Iodic
acid
Water
-Hydroxy carbonyl compounds are cleaved to a carboxylic acid and a carbonyl compound:
O
O
RCCR2 HIO4
RCOH
R2C
O HIO3
OH
-Hydroxy
carbonyl
compound
Periodic
acid
Carboxylic
acid
Carbonyl
compound
Iodic
acid
When three contiguous carbons bear hydroxyl groups, two moles of periodate are
consumed per mole of carbohydrate and the central carbon is oxidized to a molecule of
formic acid:
O
R2C
CH
CR2 2HIO4
HO
OH
OH
Points at which
cleavage occurs
Periodic
acid
R2C
O HCOH R2C
Carbonyl
compound
Formic
acid
O 2HIO3
Carbonyl
compound
Iodic
acid
Ether and acetal functions are not affected by the reagent.
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CHAPTER TWENTY-FIVE
Carbohydrates
The use of periodic acid oxidation in structure determination can be illustrated by
a case in which a previously unknown methyl glycoside was obtained by the reaction of
D-arabinose with methanol and hydrogen chloride. The size of the ring was identified as
five-membered because only one mole of periodic acid was consumed per mole of glycoside and no formic acid was produced. Were the ring six-membered, two moles of
periodic acid would be required per mole of glycoside and one mole of formic acid would
be produced.
HOCH2 O
H
OH
O
4
HO
H H
HO
HO OCH
3
2
3
OH
H
Only one site for periodic acid
cleavage in methyl
-D-arabinofuranoside
1
OCH3
Two sites of periodic acid
cleavage in methyl
-D-arabinopyranoside,
C-3 lost as formic acid
PROBLEM 25.17 Give the products of periodic acid oxidation of each of the following. How many moles of reagent will be consumed per mole of substrate in
each case?
(d)
(a) D-Arabinose
CH2OH
HO
H
(b) D-Ribose
O
(c) Methyl -D-glucopyranoside
OCH3
H OH
H H
H
OH
SAMPLE SOLUTION (a) The -hydroxy aldehyde unit at the end of the sugar
chain is cleaved, as well as all the vicinal diol functions. Four moles of periodic
acid are required per mole of D-arabinose. Four moles of formic acid and one mole
of formaldehyde are produced.
CH
D-Arabinose, showing
points of cleavage by
periodic acid; each
cleavage requires one
equivalent of HIO4.
HO
C
O
H
H
C
OH
H
C
OH
4HIO4
CH2OH
HCO2H
Formic acid
HCO2H
Formic acid
HCO2H
Formic acid
HCO2H
Formic acid
H2C
O
Formaldehyde
25.24 SUMMARY
Section 25.1
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Carbohydrates are marvelous molecules! In most of them, every carbon
bears a functional group, and the nature of the functional groups changes
as the molecule interconverts between open-chain and cyclic hemiacetal
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25.24
Summary
1007
forms. Any approach to understanding carbohydrates must begin with
structure.
Carbohydrates are polyhydroxy aldehydes and ketones. Those derived
from aldehydes are classified as aldoses; those derived from ketones are
ketoses.
Section 25.2
Fischer projections and D–L notation are commonly used to describe carbohydrate stereochemistry. The standards are the enantiomers of glyceraldehyde.
CHO
OH
H
CHO
H
HO
CH2OH
D-()-Glyceraldehyde
CH2OH
L-()-Glyceraldehyde
Section 25.3
Aldotetroses have two stereogenic centers, so four stereoisomers are possible. They are assigned to the D or the L series according to whether the
configuration at their highest numbered stereogenic center is analogous
to D- or L-glyceraldehyde, respectively. Both hydroxyl groups are on the
same side of the Fischer projection in erythrose, but on opposite sides in
threose. The Fischer projections of D-erythrose and D-threose are shown
in Figure 25.2.
Section 25.4
Of the eight stereoisomeric aldopentoses, Figure 25.2 shows the Fischer
projections of the D-enantiomers (D-ribose, D-arabinose, D-xylose, and
D-lyxose). Likewise, Figure 25.2 gives the Fischer projections of the eight
D-aldohexoses.
Section 25.5
The aldohexoses are allose, altrose, glucose, mannose, gulose, idose,
galactose, and talose. The mnemonic “All altruists gladly make gum in
gallon tanks” is helpful in writing the correct Fischer projection for each
one.
Sections
25.6–25.7
Most carbohydrates exist as cyclic hemiacetals. Cyclic acetals with fivemembered rings are called furanose forms; those with six-membered
rings are called pyranose forms.
HOCH2 O
H
H H
H OH
OH
OH
-D-Ribofuranose
H
H
HOCH2
HO
HO
O
OH
H
H
OH
H
-D-Glucopyranose
The anomeric carbon in a cyclic acetal is the one attached to two oxygens. It is the carbon that corresponds to the carbonyl carbon in the openchain form. The symbols and refer to the configuration at the
anomeric carbon.
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CHAPTER TWENTY-FIVE
Carbohydrates
Section 25.8
A particular carbohydrate can interconvert between furanose and pyranose forms and between the and configuration of each form. The
change from one form to an equilibrium mixture of all the possible hemiacetals causes a change in optical rotation called mutarotation.
Section 25.9
Ketoses are characterized by the ending -ulose in their name. Most naturally
occurring ketoses have their carbonyl group located at C-2. Like aldoses,
ketoses cyclize to hemiacetals and exist as furanose or pyranose forms.
Sections
25.10–25.12
Structurally modified carbohydrates include deoxy sugars, amino
sugars, and branched-chain carbohydrates.
Section 25.13 Glycosides are acetals, compounds in which the anomeric hydroxyl group
has been replaced by an alkoxy group. Glycosides are easily prepared by
allowing a carbohydrate and an alcohol to stand in the presence of an
acid catalyst.
D-Glucose
ROH
H
HOCH2
HO
HO
O
OR
H2O
OH
A glycoside
Sections
25.14–25.15
Disaccharides are carbohydrates in which two monosaccharides are
joined by a glycoside bond. Polysaccharides have many monosaccharide
units connected through glycosidic linkages. Complete hydrolysis of
disaccharides and polysaccharides cleaves the glycoside bonds, yielding
the free monosaccharide components.
Section 25.16 Carbohydrates and proteins that are connected by a chemical bond are
called glycoproteins and often occur on the surfaces of cells. They play
an important role in the recognition events connected with the immune
response.
Sections
25.17–25.24
Carbohydrates undergo chemical reactions characteristic of aldehydes and
ketones, alcohols, diols, and other classes of compounds, depending on
their structure. A review of the reactions described in this chapter is presented in Table 25.2. Although some of the reactions have synthetic value,
many of them are used in analysis and structure determination.
PROBLEMS
25.18 Refer to the Fischer projection of D-()-xylose in Figure 25.2 (Section 25.4) and give struc-
tural formulas for
(a) ()-Xylose (Fischer projection)
(b)
D-Xylitol
(c) -D-Xylopyranose
(d) -L-Xylofuranose
(e) Methyl -L-xylofuranoside
(f)
D-Xylonic
acid (open-chain Fischer projection)
(g) -Lactone of D-xylonic acid
(h) -Lactone of D-xylonic acid
(i)
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D-Xylaric
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acid (open-chain Fischer projection)
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TABLE 25.2
Summary of Reactions of Carbohydrates
Example
Reaction (section) and comments
Transformations of the carbonyl group
Reduction (Section 25.18) The carbonyl group of aldoses and ketoses
is reduced by sodium borohydride
or by catalytic hydrogenation. The
products are called alditols.
HO
CHO
H
H
OH
H
OH
CH2OH
Oxidation with bromine (Section
25.19) When a preparative method
for an aldonic acid is required, bromine oxidation is used. The aldonic
acid is formed as its lactone. More
properly described as a reaction of
the anomeric hydroxyl group than
of a free aldehyde.
CHO
W
CHOH
W
R
or
Aldose
CH2OH
H
H
OH
H
OH
CH2OH
H2, Ni
ethanol–water
D-Arabinose
Oxidation with Benedict’s reagent
(Section 25.19) Sugars that contain
a free hemiacetal function are
called reducing sugars. They react
with copper(II) sulfate in a sodium
citrate/sodium carbonate buffer
(Benedict’s reagent) to form a red
precipitate of copper(I) oxide. Used
as a qualitative test for reducing
sugars.
HO
D-Arabinitol
CH2OH
W
CœO
W
R
CO2H
W
CHOH W
R
Cu2
Ketose
H
CHO
OH
H
OH
HO
H
HO
H
Aldonic
acid
O
O
H
H
OH
OH
H
H3C
O
HO
OH
OH
57%
CH3
6%
L-Rhamnose
Chain extension by way of cyanohydrin formation (Section 25.20)
The Kiliani–Fischer synthesis proceeds by nucleophilic addition of
HCN to an aldose, followed by conversion of the cyano group to an
aldehyde. A mixture of stereoisomers results; the two aldoses are
epimeric at C-2. Section 25.20
describes the modern version of the
Kiliani–Fischer synthesis. The example at the right illustrates the classical version.
Copper(I)
oxide
H3C
HO
Cu2O
O
H
Br2
H 2O
(80%)
L-Rhamnonolactone
CN
CHO
H
OH
H
OH
H
OH
H
NaCN
H 2O
OH
H
OH
H
OH
D-Ribose
H
OH
H
OH
H
OH
H
OH
separate
diastereomeric
lactones and
reduce
allonolactone
with sodium
amalgam
HO
OH
H
CH2OH
CHO
C
CN
HO
C
H
H
OH
H
OH
H
OH
CH2OH
CH2OH
H2O,
heat
H2O,
heat
CH2OH
H
O
HO
CH2OH
H
O
O H H
HO
H
OH
O
H H
HO
HO
H
CH2OH
D-Allose
(34%)
Allonolactone
(35–40%)
Altronolactone
(about 45%)
(Continued)
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CHAPTER TWENTY-FIVE
TABLE 25.2
Carbohydrates
Summary of Reactions of Carbohydrates (Continued)
Reaction (section) and comments
Enediol formation (Section 25.21)
Enolization of an aldose or a ketose
gives an enediol. Enediols can
revert to aldoses or ketoses with
loss of stereochemical integrity at
the -carbon atom.
Example
CHO
H
OH
CH2OH
D-Glyceraldehyde
CHOH
CH2OH
C
C
OH
O
CH2OH
CH2OH
Enediol
1,3-Dihydroxyacetone
Reactions of the hydroxyl group
Acylation (Section 25.22) Esterification of the available hydroxyl
groups occurs when carbohydrates
are treated with acylating agents.
HOCH2
O
HO
HO
HO
OH
O
OH
CH2OH
O
O O
X X
CH3COCCH3
pyridine
HOCH2
CH2OAc
O
Sucrose
AcO
AcO
OAc
AcO
(AcO CH3CO)
X
O
O
OAc
CH2OAc
O
AcOCH2
Sucrose
octaacetate (66%)
Alkylation (Section 25.22) Alkyl halides react with carbohydrates to
form ethers at the available
hydroxyl groups. An application of
the Williamson ether synthesis to
carbohydrates.
Periodic acid oxidation (Section
25.23) Vicinal diol and -hydroxy
carbonyl functions in carbohydrates
are cleaved by periodic acid. Used
analytically as a tool for structure
determination.
C6H5
O
O
HO
C6H5
O
C6H5CH2Cl
KOH
HO OCH
3
O
O
O
C6H5CH2O
C6H5CH2O OCH
3
Methyl 4,6-O-benzylidene-D-glucopyranoside
Methyl 2,3-di-O-benzyl4,6-O-benzylidene-D-glucopyranoside (92%)
CHO
H
H
H
OH
H
OH
CHO
2HIO4
CH2
O
O
HCOH HCH
Formic
acid
Formaldehyde
CHO
CH2OH
2-Deoxy-D-ribose
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Problems
1011
25.19 From among the carbohydrates shown in Figure 25.2, choose the D-aldohexoses that yield
(a) An optically inactive product on reduction with sodium borohydride
(b) An optically inactive product on oxidation with bromine
(c) An optically inactive product on oxidation with nitric acid
(d) The same enediol
25.20 Write the Fischer projection of the open-chain form of each of the following:
HO
OH
(a)
HOCH2
O
OH
O
(c)
OH
H3C
OH
HO
H
HO
CH2OH
H
O
OH
HOCH2
O
HO
OH
(b)
(d)
H H
HO
CH2OH
OH
H H
HO
OH
OH
25.21 What are the R,S configurations of the three stereogenic centers in D-ribose? (A molecular
model will be helpful here.)
25.22 From among the carbohydrates shown in Problem 25.20 choose the one(s) that
(a) Belong to the
L
series
(b) Are deoxy sugars
(c) Are branched-chain sugars
(d) Are ketoses
(e) Are furanose forms
(f) Have the configuration at their anomeric carbon
25.23 How many pentuloses are possible? Write their Fischer projections.
25.24 The Fischer projection of the branched-chain carbohydrate D-apiose has been presented in
Section 25.12.
(a) How many stereogenic centers are in the open-chain form of D-apiose?
(b) Does D-apiose form an optically active alditol on reduction?
(c) How many stereogenic centers are in the furanose forms of D-apiose?
(d) How many stereoisomeric furanose forms of D-apiose are possible? Write their
Haworth formulas.
25.25 Treatment of D-mannose with methanol in the presence of an acid catalyst yields four isomeric products having the molecular formula C7H14O6. What are these four products?
25.26 Maltose and cellobiose (Section 25.14) are examples of disaccharides derived from
glucopyranosyl units.
D-
(a) How many other disaccharides are possible that meet this structural requirement?
(b) How many of these are reducing sugars?
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CHAPTER TWENTY-FIVE
Carbohydrates
25.27 Gentiobiose has the molecular formula C12H22O11 and has been isolated from gentian root
and by hydrolysis of amygdalin. Gentiobiose exists in two different forms, one melting at 86°C
and the other at 190°C. The lower melting form is dextrorotatory ([]22
D 16°), the higher melting one is levorotatory ([]22
D 6°). The rotation of an aqueous solution of either form, however,
gradually changes until a final value of []22
D 9.6° is observed. Hydrolysis of gentiobiose is efficiently catalyzed by emulsin and produces two moles of D-glucose per mole of gentiobiose. Gentiobiose forms an octamethyl ether, which on hydrolysis in dilute acid yields 2,3,4,6-tetra-Omethyl-D-glucose and 2,3,4-tri-O-methyl-D-glucose. What is the structure of gentiobiose?
25.28 Cyanogenic glycosides are potentially toxic because they liberate hydrogen cyanide on
enzyme-catalyzed or acidic hydrolysis. Give a mechanistic explanation for this behavior for the
specific cases of
CH2OH
HO
(a)
HO
CO2H
O
OC(CH3)2
HO
HO
(b)
HO
O
OCHC6H5
HO
CN
Linamarin
CN
Laetrile
25.29 The following are the more stable anomers of the pyranose forms of D-glucose, D-mannose,
and D-galactose:
HOCH2
HO
HO
O
HO
HO
OH
HO
HOCH2 OH
O
CH2OH
O
HO
OH
HO
HO
OH
-D-Glucopyranose
(64% at equilibrium)
-D-Mannopyranose
(68% at equilibrium)
-D-Galactopyranose
(64% at equilibrium)
On the basis of these empirical observations and your own knowledge of steric effects in sixmembered rings, predict the preferred form (- or -pyranose) at equilibrium in aqueous solution
for each of the following:
(a)
D-Gulose
(c)
D-Xylose
(b)
D-Talose
(d)
D-Lyxose
25.30 Basing your answers on the general mechanism for the first stage of acid-catalyzed acetal
hydrolysis
R2COR
H, fast
R2COR
OCH3
slow
R2COR
H2O, fast
O
H
R2COR H
OH
CH3
Acetal
Hemiacetal
suggest reasonable explanations for the following observations:
(a) Methyl -D-fructofuranoside (compound A) undergoes acid-catalyzed hydrolysis some
105 times faster than methyl -D-glucofuranoside (compound B).
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Problems
CH2OH
H
O
HO
HOCH2 O
H H
CH2OH
H OH
HO OCH
3
OH
H
H
Compound A
1013
H
H OCH
3
OH
Compound B
(b) The -methyl glucopyranoside of 2-deoxy-D-glucose (compound C) undergoes hydrolysis several thousand times faster than that of D-glucose (compound D).
HOCH2
CH2OH
O
HO
HO
OCH3
HO
HO
O
OCH3
HO
Compound C
Compound D
25.31 D-Altrosan is converted to D-altrose by dilute aqueous acid. Suggest a reasonable mecha-
nism for this reaction.
O
O
OH
H2O
H
D-altrose
OH
HO
D-Altrosan
25.32 When D-galactose was heated at 165°C, a small amount of compound A was isolated:
CHO
H
OH
O
HO
HO
H
H
heat
HO
O
OH
H
OH
OH
CH2OH
D-Galactose
Compound A
The structure of compound A was established, in part, by converting it to known compounds. Treatment of A with excess methyl iodide in the presence of silver oxide, followed by hydrolysis with
dilute hydrochloric acid, gave a trimethyl ether of D-galactose. Comparing this trimethyl ether with
known trimethyl ethers of D-galactose allowed the structure of compound A to be deduced.
How many trimethyl ethers of D-galactose are there? Which one is the same as the product
derived from compound A?
25.33 Phlorizin is obtained from the root bark of apple, pear, cherry, and plum trees. It has the
molecular formula C21H24O10 and yields a compound A and D-glucose on hydrolysis in the presence of emulsin. When phlorizin is treated with excess methyl iodide in the presence of potassium
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CHAPTER TWENTY-FIVE
Carbohydrates
carbonate and then subjected to acid-catalyzed hydrolysis, a compound B is obtained. Deduce the
structure of phlorizin from this information.
OR
RO
O
CCH2CH2
OR
OH
Compound A:
Compound B:
RH
R CH3
25.34 Emil Fischer’s determination of the structure of glucose was carried out as the nineteenth
century ended and the twentieth began. The structure of no other sugar was known at that time,
and none of the spectroscopic techniques that aid organic analysis were then available. All Fischer
had was information from chemical transformations, polarimetry, and his own intellect. Fischer
realized that ()-glucose could be represented by 16 possible stereostructures. By arbitrarily
assigning a particular configuration to the stereogenic center at C-5, the configurations of C-2,
C-3, and C-4 could be determined relative to it. This reduces the number of structural possibilities to eight. Thus, he started with a structural representation shown as follows, in which C-5 of
()-glucose has what is now known as the D configuration.
CHO
CHOH
CHOH
CHOH
H
OH
CH2OH
Eventually, Fischer’s arbitrary assumption proved to be correct, and the structure he proposed for
()-glucose is correct in an absolute as well as a relative sense. The following exercise uses information available to Fischer and leads you through a reasoning process similar to that employed in
his determination of the structure of ()-glucose. See if you can work out the configuration of
()-glucose from the information provided, assuming the configuration of C-5 as shown here.
1. Chain extension of the aldopentose ()-arabinose by way of the derived cyanohydrin gave
a mixture of ()-glucose and ()-mannose.
2. Oxidation of ()-arabinose with warm nitric acid gave an optically active aldaric acid.
3. Both ()-glucose and ()-mannose were oxidized to optically active aldaric acids with
nitric acid.
4. There is another sugar, ()-gulose, that gives the same aldaric acid on oxidation as does
()-glucose.
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